Preschool children's coping responses and outcomes in the vaccination context: child and caregiver transactional and longitudinal relationships.
This article, based on 2 companion studies, presents an in-depth analysis of preschoolers coping with vaccination pain. Study 1 used an autoregressive cross-lagged path model to investigate the dynamic and reciprocal relationships between young children's coping responses (how they cope with pain and distress) and coping outcomes (pain behaviors) at the preschool vaccination. Expanding on this analysis, study 2 then modeled preschool coping responses and outcomes using both caregiver and child variables from the child's 12-month vaccination (n = 548), preschool vaccination (n = 302), and a preschool psychological assessment (n = 172). Summarizing over the 5 path models and post hoc analyses over the 2 studies, novel transactional and longitudinal pathways predicting preschooler coping responses and outcomes were elucidated. Our research has provided empirical support for the need to differentiate between coping responses and coping outcomes: 2 different, yet interrelated, components of "coping." Among our key findings, the results suggest that a preschooler's ability to cope is a powerful tool to reduce pain-related distress but must be maintained throughout the appointment; caregiver behavior and poorer pain regulation from the 12-month vaccination appointment predicted forward to preschool coping responses and/or outcomes; robust concurrent relationships exist between caregiver behaviors and both child coping responses and outcomes, and finally, caregiver behaviors during vaccinations are not only critical to both child pain coping responses and outcomes in the short- and long-term but also show relationships to broader child cognitive abilities as well.


Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays.
Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin-producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®-vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two-step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®-vaccination. Using arrays of more than 9000 full-length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first-degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α-MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®-induced NT1.


Age at first sex and HIV infection in rural Zimbabwe.
Beginning sexual activity introduces an individual to the risk of acquiring sexually transmitted infections. In this study, cross-sectional behavioral data linked to HIV-status from 4,138 men and 4,948 women interviewed in rural Zimbabwe are analyzed to investigate the distribution and consequences of early first sex. We find that age at first sex (at a median age of 19 years for males and 18 years for females) has declined among males over the past 30 years but increased recently among females. Those in unskilled employment, those not associated with a church, and women without a primary education begin to have sex earlier than others. Early sexual debut before marriage precedes a lifetime of greater sexual activity but with more consistent condom use. Women who begin to have sex earlier than others of their age are more likely to be infected with HIV. This finding can be explained by their having a greater lifetime number of sexual partners than those whose first sexual experience occurs later.


Predicting Deletion of Chromosomal Arms 1p/19q in Low-Grade Gliomas from MR Images Using Machine Intelligence.
Several studies have linked codeletion of chromosome arms 1p/19q in low-grade gliomas (LGG) with positive response to treatment and longer progression-free survival. Hence, predicting 1p/19q status is crucial for effective treatment planning of LGG. In this study, we predict the 1p/19q status from MR images using convolutional neural networks (CNN), which could be a non-invasive alternative to surgical biopsy and histopathological analysis. Our method consists of three main steps: image registration, tumor segmentation, and classification of 1p/19q status using CNN. We included a total of 159 LGG with 3 image slices each who had biopsy-proven 1p/19q status (57 non-deleted and 102 codeleted) and preoperative postcontrast-T1 (T1C) and T2 images. We divided our data into training, validation, and test sets. The training data was balanced for equal class probability and was then augmented with iterations of random translational shift, rotation, and horizontal and vertical flips to increase the size of the training set. We shuffled and augmented the training data to counter overfitting in each epoch. Finally, we evaluated several configurations of a multi-scale CNN architecture until training and validation accuracies became consistent. The results of the best performing configuration on the unseen test set were 93.3% (sensitivity), 82.22% (specificity), and 87.7% (accuracy). Multi-scale CNN with their self-learning capability provides promising results for predicting 1p/19q status non-invasively based on T1C and T2 images. Predicting 1p/19q status non-invasively from MR images would allow selecting effective treatment strategies for LGG patients without the need for surgical biopsy.


Indirect effects drive evolutionary responses to global change.
Anthropogenic environmental changes pose significant threats to plant and animal populations. These changes also may affect the evolution of natural populations either directly or indirectly by altering the outcome of species interactions that are important drivers of evolution. This latter indirect pathway may be especially important for evolutionary responses to elevated atmospheric CO2 concentrations (eCO2), which appear to have minimal direct effects on plant evolution but have large effects on interspecific interactions, such as competition. We manipulated competitive and CO2 environments of experimental Arabidopsis thaliana populations to test whether eCO2 alters evolutionary trajectories indirectly by altering selection imposed by competitors. We found that interspecific competition increased selection on growth traits, reduced heritabilities, and altered genetic covariances between traits and that the magnitude of these effects depended upon the CO2 environment. Although eCO2 had minimal direct effects on evolutionary processes, eCO2 typically reduced the strength of selection imposed by competitors and, therefore, relaxed selection on plant traits when competitors were present. Our results indicate that global changes may affect plant evolution indirectly by altering competitive interactions and underscore the importance of conducting research in natural communities when attempting to predict population responses to global change.


Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia.
Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML.


Delphinid behavioral responses to incidental mid-frequency active sonar.
Opportunistic observations of behavioral responses by delphinids to incidental mid-frequency active (MFA) sonar were recorded in the Southern California Bight from 2004 through 2008 using visual focal follows, static hydrophones, and autonomous recorders. Sound pressure levels were calculated between 2 and 8 kHz. Surface behavioral responses were observed in 26 groups from at least three species of 46 groups out of five species encountered during MFA sonar incidents. Responses included changes in behavioral state or direction of travel, changes in vocalization rates and call intensity, or a lack of vocalizations while MFA sonar occurred. However, 46% of focal groups not exposed to sonar also changed their behavior, and 43% of focal groups exposed to sonar did not change their behavior. Mean peak sound pressure levels when a behavioral response occurred were around 122 dB re: 1 μPa. Acoustic localizations of dolphin groups exhibiting a response gave insight into nighttime movement patterns and provided evidence that impacts of sonar may be mediated by behavioral state. The lack of response in some cases may indicate a tolerance of or habituation to MFA sonar by local populations; however, the responses that occur at lower received levels may point to some sensitization as well.


Dissolution of the metal sensitizers Ni, Be, Cr in artificial sweat to improve estimates of dermal bioaccessibility.
Dermal exposure to sensitizing metals is a serious occupational and public health problem. The usual approach to dermal exposure assessment is to process samples by chemical methods that use reactants to digest the metal particles and quantify the mass. In the case of dermal exposure assessment, these reactants are not representative of the skin surface film liquids and hence, may overestimate bioaccessibility. We hypothesize that the amount and form of sensitizer on a sample that leaches in a biological fluid, as can be estimated using artificial sweat, may be a more relevant metric for assessing health risks. Beryllium metal (Be), nickel metal (Ni), and chromium carbide (Cr3C2) particles were characterized and masses of sensitizing ions were measured using established reactant-assisted digestion procedures and extraction in artificial sweat under physiologically relevant conditions. Chromium ions released into artificial sweat were speciated to understand valence states. The ratios of the fraction of metal dissolved in artificial sweat relative to that dissolved by chemical-specific reactants were 1/2 (Be), 1/108 (Ni), and 1/2500 (Cr). The divalent Be and Ni cations were stable in artificial sweat over time (did not precipitate) whereas hexavalent chromium [Cr(VI)] ions decayed over time. Further analysis using speciated isotope dilution mass spectrometry revealed that the decay of Cr(VI) was accompanied by the formation of Cr(III) in the sweat model. Use of reactant-assisted analytical chemistry to quantify amounts of metal sensitizers on samples could overestimate biologically relevant exposure. In addition to mass, the valence state also influences penetration through the outer stratum corneum of the skin and is an important consideration when assessing exposure to complex sensitizers such as Cr which have multiple valence states with differing penetration efficiencies.


A Canadian multicenter trial assessing memory and executive functions in patients with schizophrenia spectrum disorders treated with olanzapine.
Serial verbal learning task (explicit long-term memory) and verbal fluency (generation of a response) are tests that are usually severely impaired in schizophrenia. Despite the growing literature supporting the clinical efficacy of olanzapine, psychiatrists still question its cognitive consequences. This study assessed the efficacy of olanzapine on neurocognitive functioning. Patients (N = 134) meeting diagnostic criteria for schizophrenia, schizophreniform, or schizoaffective disorders began an 8-week, open-label olanzapine treatment at a dose of 5 mg/d, which was increased to 10 mg/d after 1 week. Daily dosage was subsequently adjusted between 5 and 20 mg/d based on individual clinical status. All previous antipsychotics were tapered and discontinued during the first 2 weeks of the study. Neuropsychologic assessments were carried out at baseline and at 4 and 8 weeks. Explicit long-term memory was assessed with the Rey Auditory-Verbal Learning Test: the average immediate recall score significantly improved (P < 0.001), as did the delayed recall score (P < 0.001). The average total score on category fluency improved from 34.6 words at baseline to 37.6 words at end point (P < 0.0001). Time on both Trail A and B making tasks significantly decreased (P < 0.0001). Lack of a control arm makes it impossible to exclude a practice effect as an explanation for the enhanced cognitive performance, although the Word List Recall test represents one of the better resources to avoid a practice effect. After switching to olanzapine, there was a statistically significant improvement of cognitive function in the 3 main domains tested and no significant worsening of any memory or executive function measure.


Prevalence of toxoplasma myocarditis in patients with the acquired immunodeficiency syndrome.
To evaluate the prevalence of cardiac toxoplasmosis in a series of 182 necropsies performed between 1987 and 1991 on patients infected with the human immunodeficiency virus (HIV), to correlate this prevalence with the ante mortem diagnosis of cardiac involvement, and to assess the role of such cardiac lesions in the immediate cause of death. Complete necropsies of 182 HIV-infected patients (48 women, 134 men) were performed consecutively between 1987 and 1991. Risk factors, identified in 174 cases, included drug abuse (111/182), homosexuality (51/182), and blood transfusions (12/182). 16 samples were systematically obtained from each heart for histological study. If trophozoites or lymphocytic myocarditis were seen, immunohistochemical investigations were carried out with polyclonal antibodies for Toxoplasma gondii. An ultrastructural study was performed in four patients with toxoplasma myocarditis. Myocardial lesions were defined by the Dallas classification. Clinical data (and information on electrocardiograms and echocardiograms) were obtained from medical records. Cardiac toxoplasmosis was diagnosed at necropsy in 21 (12%) patients. Cardiac lesions were associated with toxoplasmic encephalitis in 18 patients and were solitary in three patients. Acute diffuse myocarditis was present in 6/21, rare foci of myocarditis were seen in 8/21, and intramyocytic toxoplasmic cysts without any inflammatory reaction or necrosis were seen in 4/21. Anti-toxoplasma immunolabelling showed cardiac toxoplasmosis in three patients with lymphocytic myocarditis. Particles with the ultrastructural characteristics of Toxoplasma gondii trophozoites were seen in four cases. Six patients had presented with cardiac symptoms, confirmed by electrocardiographic and echocardiographic abnormalities during their disease course, and their cardiac lesions were directly responsible for the death. Cardiac toxoplasmosis was common in this necropsy series of HIV-infected patients. Cardiac toxoplasmosis had been suspected clinically in four patients. Myocardial lesions were generally asymptomatic and were not discovered until necropsy. Solitary cardiac involvement was not uncommon reflecting parasite reactivation at a myocardial site. The incidence of cardiac toxoplasmosis in this group of immunodepressed subjects from an area with a high prevalence of this parasitic disease justifies regular follow up of such patients by electrocardiography and echocardiography as well as immediate administration of anti-toxoplasma treatment should sudden heart failure occur.


Implications of Abnormal Troponin Levels With Normal Right Ventricular Function in Normotensive Patients With Acute Pulmonary Embolism.
Among patients with pulmonary embolism (PE), various permutations of normal or abnormal cardiac troponin results and normal or abnormal echocardiographic right ventricular function are encountered in clinical practice. We aimed to explore whether there is a true gradient of risk based on troponin and echocardiographic results. This study included normotensive patients with PE from the PROgnosTic valuE of CT scan in hemodynamically stable patients with acute symptomatic pulmonary embolism (PROTECT) study. Patients were categorized as having -Troponin/-Echo, -Troponin/+Echo, +Troponin/-Echo, and +Troponin/+Echo. The primary outcome was 30-day "complicated course," including death from any cause, hemodynamic collapse, or recurrent PE. Secondary outcomes included individual adverse event rates. Of the 834 patients who had echocardiographic and troponin results, 569 patients (68%) had -Troponin/-Echo, 126 patients (15%) had -Troponin/+Echo, 74 patients (8.9%) had +Troponin/-Echo, and 65 patients (7.8%) had +Troponin/+Echo. The incidence of 30-day complicated course was 4.6% in patients with -Troponin/-Echo, 11.9% in patients with -Troponin/+Echo, 13.5% in patients with +Troponin/-Echo, and 16.9% in patients with +Troponin/+Echo (P for trend <0.001). In the subgroup of patients with a high-risk sPESI (i.e., intermediate-risk according to the ESC guidelines) (n = 527), the incidence of 30-day complicated course was 14.9% in patients with -Troponin/+Echo, 18.5% in patients with +Troponin/-Echo, and 17.5% in patients with +Troponin/+Echo (P for trend <0.01). In patiens with PE, there seems to be a risk gradient based on troponin and echocardiographic results. This study did not detect a significant risk difference in those with +Troponin/-Echo compared with -Troponin/+Echo.


Ascorbic acid provides protection for human chondrocytes against oxidative stress.
Oxidative stress is considered to be an important cause of dysfunction in chondrocytes and articular cartilage degradation, which leads to the pathogenesis of osteoarthritis (OA) and cartilage aging. The present study aimed to assess the effects of the widely applied antioxidant, ascorbic acid (AA), on human chondrocytes against hydrogen peroxide (H2O2) in vitro. Using annexin V‑fluorescein isothiocyanate, 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyl tetrazolium bromide and senescence‑associated β‑galactosidase assays, the present study identified that AA reduced apoptosis, reduced the loss of viability and markedly decreased H2O2‑mediated senescence in cells treated with H2O2. Furthermore, AA not only stimulated the expression levels of collagens and proteoglycans, but also inhibited the differentiation of chondrocytes under conditions of oxidative stress. In addition, reverse transcription‑quantitative polymerase chain reaction and western blotting demonstrated that AA decreased the activity of nrf2, NF‑κB, AP1 and matrix metalloproteinase‑3, which is stimulated by H2O2. In conclusion, AA efficiently protected human chondrocytes against damage induced by H2O2 by regulating multiple regulatory pathways.


Financial ties between DSM-IV panel members and the pharmaceutical industry.
Increasing attention has been given to the transparency of potential conflicts of interest in clinical medicine and biomedical sciences, particularly in journal publishing and science advisory panels. The authors examined the degree and type of financial ties to the pharmaceutical industry of panel members responsible for revisions of the Diagnostic and Statistical Manual of Mental Disorders(DSM). By using multimodal screening techniques the authors investigated the financial ties to the pharmaceutical industry of 170 panel members who contributed to the diagnostic criteria produced for the DSM-IV and the DSM-IV-TR. Of the 170 DSM panel members 95 (56%) had one or more financial associations with companies in the pharmaceutical industry. One hundred percent of the members of the panels on 'Mood Disorders' and 'Schizophrenia and Other Psychotic Disorders' had financial ties to drug companies. The leading categories of financial interest held by panel members were research funding (42%), consultancies (22%) and speakers bureau (16%). Our inquiry into the relationships between DSM panel members and the pharmaceutical industry demonstrates that there are strong financial ties between the industry and those who are responsible for developing and modifying the diagnostic criteria for mental illness. The connections are especially strong in those diagnostic areas where drugs are the first line of treatment for mental disorders. Full disclosure by DSM panel members of their financial relationships with for-profit entities that manufacture drugs used in the treatment of mental illness is recommended.


Identification of a class 3 aldehyde dehydrogenase in human saliva and increased levels of this enzyme, glutathione S-transferases, and DT-diaphorase in the saliva of subjects who continually ingest large quantities of coffee or broccoli.
Human saliva was tested for the presence of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferases alpha, mu, and pi, and DT-diaphorase, enzymes that are known to catalyze the biotransformation of many xenobiotics, including some that are carcinogens and some that are antineoplastic agents. Each of these enzymes was found to be present in this fluid. Inducers of these enzymes are known to be abundantly present in the human diet, especially in certain vegetables and fruits. Further investigation revealed that the salivary content of these enzymes rapidly, coordinately, and markedly increased upon daily consumption of relatively large amounts of coffee or broccoli. The enzyme activities of interest rapidly returned to basal levels when these substances were removed from the diet. Given the important role that cytosolic class 3 aldehyde dehydrogenase, the glutathione S-transferases, and DT-diaphorase are thought to play in determining the carcinogenic potential of some cancer-producing agents as well as the cytotoxic potential of some antineoplastic agents, and assuming that their salivary levels reflect their tissue levels, quantification of the salivary content of one or more of these enzymes, a noninvasive and relatively easy undertaking, could be useful in: (a) preliminarily assessing the chemopreventive potential of various diets and drugs; (b) establishing the optimal dose and schedule in Phase I clinical trials for any putatively chemopreventive diets or drugs of interest; and (c) the rational selection and use of chemotherapeutic agents, since several are inactivated, and a few are activated, by these enzymes; alternatively, the antineoplastic agent could be selected first and then a diet that enables the agent to achieve its full therapeutic potential would be selected based on whether high or low enzyme activity would be favorable in that regard. Such measurements may also be useful as an indicator when exposure to carcinogenic/teratogenic/otherwise toxic environmental/industrial/dietary agents that induce these enzymes is suspected.


Supramodal representations of perceived emotions in the human brain.
Basic emotional states (such as anger, fear, and joy) can be similarly conveyed by the face, the body, and the voice. Are there human brain regions that represent these emotional mental states regardless of the sensory cues from which they are perceived? To address this question, in the present study participants evaluated the intensity of emotions perceived from face movements, body movements, or vocal intonations, while their brain activity was measured with functional magnetic resonance imaging (fMRI). Using multivoxel pattern analysis, we compared the similarity of response patterns across modalities to test for brain regions in which emotion-specific patterns in one modality (e.g., faces) could predict emotion-specific patterns in another modality (e.g., bodies). A whole-brain searchlight analysis revealed modality-independent but emotion category-specific activity patterns in medial prefrontal cortex (MPFC) and left superior temporal sulcus (STS). Multivoxel patterns in these regions contained information about the category of the perceived emotions (anger, disgust, fear, happiness, sadness) across all modality comparisons (face-body, face-voice, body-voice), and independently of the perceived intensity of the emotions. No systematic emotion-related differences were observed in the overall amplitude of activation in MPFC or STS. These results reveal supramodal representations of emotions in high-level brain areas previously implicated in affective processing, mental state attribution, and theory-of-mind. We suggest that MPFC and STS represent perceived emotions at an abstract, modality-independent level, and thus play a key role in the understanding and categorization of others' emotional mental states.


Physically correct theoretical prism waveguide coupler model.
We develop new generalized four-wave-model-based waveguide mode equations for both isotropic and anisotropic systems by taking into account the influence of the incident light. These new mode equations eliminate the inherent deficiency in the conventional waveguide model, in which the action of incident light was neglected. Further, a peak-value-search (PVS) numerical method is developed to solve the four-wave-model-based mode equations. The PVS method has significant advantages in that accurate refractive index and thickness can be obtained without prior knowledge of the thickness of the air gap.


An optical system for monochromatic photography of the electron corona.
Description and the performance are given of a reflecting telescope and accessory optics used to feed a Lyot Halpha tunable filter, and then to obtain monochromatic images near the Halpha wavelength. The instrumentation has been designed for coronal photography to be taken inside and outside the line during a total eclipse.


Recurrent cholangitis associated with biliary sludge and Phrygian cap anomaly diagnosed by magnetic resonance imaging and magnetic resonance cholangiopancreatography despite normal ultrasound and computed tomography.
A 31-year-old woman presented with a one and half years' history of intermittent right upper quadrant (RUQ) pain, high fever and severely painful, warm and reddish swollen skin lesions on the fingers. Acute attack resolution occurred within 2 weeks after treatment with non-specific antibiotics. Low-grade fever (around 37.5 degrees C) and less painful swellings continued for 6 months after each attack. Abdominal ultrasound and computed tomography (CT) scans did not show any abnormality during the attacks. Biopsy of the skin lesions after the second attack revealed lymphocytic vasculitis. All laboratory studies including rheumatologic serology panel were normal. One month after the complete resolution of the second attack, the patient was observed to have high fever, the same skin lesions on the fingers as at the initial stage, nausea and marked abdominal pain in the RUQ. Routine laboratory studies including complete blood count, liver function tests and serum amylase and lipase levels were normal. An abdominal CT scan revealed a slight thickening of the gallbladder wall (3.9 mm). Two weeks later, abdominal magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) were performed because of persistent abdominal pain. They revealed both biliary tract and pancreatic gland alterations consistent with past cholangitis and pancreatitis with coexisting Phrygian cap anomaly and biliary sludge on the neck of the gallbladder.


Soft tissue expansion before vertical ridge augmentation: Inflatable silicone balloons or self-filling osmotic tissue expanders?
Recent advances in periodontal plastic surgical procedures allow the clinician to reconstruct deficient alveolar ridges in more predictable ways than previously possible. Placement of implant/s in resorbed ridges poses numerous challenges to the clinician for successful esthetic and functional rehabilitation. The reconstruction frequently utilizes one or combination of periodontal plastic surgical procedures in conjunction with autogenous bone grafting, allogenic bone block grafting, ridge split techniques, distraction osteogenesis, or guided bone regeneration (GBR) for most predictable outcomes. Current surgical modalities used in reconstruction of alveolar ridge (horizontal and/or vertical component) often involve the need of flap transfer. Moreover, there is compromise in tissue integrity and color match owing to different surgical site and the tissue utilized is insufficient in quantity leading to post surgical graft exposition and/or loss of grafted bone. Soft tissue expansion (STE) by implantation of inflatable silicone balloon or self filling osmotic tissue expanders before reconstructive surgery can overcome these disadvantages and certainly holds a promise for effective method for generation of soft tissue thereby achieving predictable augmentation of deficient alveolar ridges for the implant success. This article focuses and compares these distinct tissue expanders for their clinical efficacy of achieving excess tissue that predominantly seems to be prerequisite for ridge augmentation which can be reasonably followed by successful placement of endosseous fixtures.


A case of cerebral venous thrombosis as the presenting sign of occult prostate cancer.
Cerebral venous thrombosis (CVT) is a distinct disorder with highly variable symptoms and courses. Malignancy is known to be one of the predisposing factors of CVT. We present the case of a 69-year-old man with sudden behavioral changes. Brain MRI, magnetic resonance venography, and positive D-dimer assay confirmed the presence of CVT. The work-up for detecting the cause of the CVT revealed occult prostate cancer. Occult malignancy including prostate cancer should be strongly suspected in older patients with idiopathic CVT.


Sequence mining and transcript profiling to explore cyst nematode parasitism.
Cyst nematodes are devastating plant parasites that become sedentary within plant roots and induce the transformation of normal plant cells into elaborate feeding cells with the help of secreted effectors, the parasitism proteins. These proteins are the translation products of parasitism genes and are secreted molecular tools that allow cyst nematodes to infect plants. We present here the expression patterns of all previously described parasitism genes of the soybean cyst nematode, Heterodera glycines, in all major life stages except the adult male. These insights were gained by analyzing our gene expression dataset from experiments using the Affymetrix Soybean Genome Array GeneChip, which contains probeset sequences for 6,860 genes derived from preparasitic and parasitic H. glycines life stages. Targeting the identification of additional H. glycines parasitism-associated genes, we isolated 633 genes encoding secretory proteins using algorithms to predict secretory signal peptides. Furthermore, because some of the known H. glycines parasitism proteins have strongest similarity to proteins of plants and microbes, we searched for predicted protein sequences that showed their highest similarities to plant or microbial proteins and identified 156 H. glycines genes, some of which also contained a signal peptide. Analyses of the expression profiles of these genes allowed the formulation of hypotheses about potential roles in parasitism. This is the first study combining sequence analyses of a substantial EST dataset with microarray expression data of all major life stages (except adult males) for the identification and characterization of putative parasitism-associated proteins in any parasitic nematode. We have established an expression atlas for all known H. glycines parasitism genes. Furthermore, in an effort to identify additional H. glycines genes with putative functions in parasitism, we have reduced the currently known 6,860 H. glycines genes to a pool of 788 most promising candidate genes (including known parasitism genes) and documented their expression profiles. Using our approach to pre-select genes likely involved in parasitism now allows detailed functional analyses in a manner not feasible for larger numbers of genes. The generation of the candidate pool described here is an important enabling advance because it will significantly facilitate the unraveling of fascinating plant-animal interactions and deliver knowledge that can be transferred to other pathogen-host systems. Ultimately, the exploration of true parasitism genes verified from the gene pool delineated here will identify weaknesses in the nematode life cycle that can be exploited by novel anti-nematode efforts.


Hemodynamic responses to vasopressinergic antagonism in water-deprived conscious rats.
Experiments were performed on conscious, chronically instrumented rats to determine the role of arginine vasopressin (AVP) on the systemic and regional hemodynamic effects of 48-h water deprivation. Arterial and venous catheters as well as pulsed Doppler flow probes were implanted in rats to measure cardiac output (CO), mesenteric blood flow (MBF), renal blood flow (RBF), or hindquarter blood flow (HQBF). After adequate recovery from surgey, euhydrated animals were administered a specific V1-vasopressinergic antagonist [d(CH2)5Tyr(Me)AVP, 10 micrograms/kg iv], a combined V1, V2-antagonist [d(CH2)5DTyr(Et)VAVP, 30 micrograms/kg iv], or saline vehicle (100 microliter/100 g). Neither antagonist was associated with any change in mean arterial blood pressure (MABP), heart rate (HR), systemic or regional flow or vascular resistance. All animals were subsequently water deprived for 48 h, at which time the experiments were repeated. Dehydration was associated with an increase in plasma AVP levels, hematocrit, and MABP but with a decrease in HR. Administration of either the combined V1, V2-antagonist or vehicle had no effect on any systemic or regional hemodynamic variables measured after 48-h dehydration. In contrast, although MABP, CO, MBF, and RBF were unaffected, V1-antagonism resulted in elevated HR, increased HQBF, and decreased hindquarter vascular resistance. In conclusion, AVP does not have a major effect on systemic hemodynamics in the dehydrated rat. However, certain beds may be affected by the relatively moderate levels of plasma AVP elicited during dehydration.


Methylene blue attenuates traumatic brain injury-associated neuroinflammation and acute depressive-like behavior in mice.
Traumatic brain injury (TBI) is associated with cerebral edema, blood brain barrier breakdown, and neuroinflammation that contribute to the degree of injury severity and functional recovery. Unfortunately, there are no effective proactive treatments for limiting immediate or long-term consequences of TBI. Therefore, the objective of this study was to determine the efficacy of methylene blue (MB), an antioxidant agent, in reducing inflammation and behavioral complications associated with a diffuse brain injury. Here we show that immediate MB infusion (intravenous; 15-30 minutes after TBI) reduced cerebral edema, attenuated microglial activation and reduced neuroinflammation, and improved behavioral recovery after midline fluid percussion injury in mice. Specifically, TBI-associated edema and inflammatory gene expression in the hippocampus were significantly reduced by MB at 1 d post injury. Moreover, MB intervention attenuated TBI-induced inflammatory gene expression (interleukin [IL]-1β, tumor necrosis factor α) in enriched microglia/macrophages 1 d post injury. Cell culture experiments with lipopolysaccharide-activated BV2 microglia confirmed that MB treatment directly reduced IL-1β and increased IL-10 messenger ribonucleic acid in microglia. Last, functional recovery and depressive-like behavior were assessed up to one week after TBI. MB intervention did not prevent TBI-induced reductions in body weight or motor coordination 1-7 d post injury. Nonetheless, MB attenuated the development of acute depressive-like behavior at 7 d post injury. Taken together, immediate intervention with MB was effective in reducing neuroinflammation and improving behavioral recovery after diffuse brain injury. Thus, MB intervention may reduce life-threatening complications of TBI, including edema and neuroinflammation, and protect against the development of neuropsychiatric complications.


Cardiovascular and noncardiovascular mortality among patients starting dialysis.
Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123,407]) was compared with the European general population (Eurostat). Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and 10,183,322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43). Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality.


Candidate metabolic network states in human mitochondria. Impact of diabetes, ischemia, and diet.
The human mitochondrial metabolic network was recently reconstructed based on proteomic and biochemical data. Linear programming and uniform random sampling were applied herein to identify candidate steady states of the metabolic network that were consistent with the imposed physico-chemical constraints and available experimental data. The activity of the mitochondrion was studied under four metabolic conditions: normal physiologic, diabetic, ischemic, and dietetic. Pairwise correlations between steady-state reaction fluxes were calculated in each condition to evaluate the dependence among the reactions in the network. Applying constraints on exchange fluxes resulted in predictions for intracellular fluxes that agreed with experimental data. Analyses of the steady-state flux distributions showed that the experimentally observed reduced activity of pyruvate dehydrogenase in vivo could be a result of stoichiometric constraints and therefore would not necessarily require enzymatic inhibition. The observed changes in the energy metabolism of the mitochondrion under diabetic conditions were used to evaluate the impact of previously suggested treatments. The results showed that neither normalized glucose uptake nor decreased ketone body uptake have a positive effect on the mitochondrial energy metabolism or network flexibility. Taken together, this study showed that sampling of the steady-state flux space is a powerful method to investigate network properties under different conditions and provides a basis for in silico evaluations of effects of potential disease treatments.


How do nurses working in hospital accident and emergency departments perceive local general practitioners? A study in six English hospitals.
One hundred and forty-three Accident and Emergency nurses working in six departments in contrasting districts of England completed questionnaires about their perception of local general practice. Much of general practice was perceived as being performed unsatisfactorily. Out-of-hours accessibility, caring for patients with 'difficult' or psychosocial problems, advising on health service usage, and minor surgery and first aid were all thought to be performed particularly badly. In addition, there was considerable inter-district variation with the views expressed in inner London being especially negative. To some extent these views may reflect real short-comings in general practice, but they are likely to be coloured by the disproportionate experience A&E departments inevitably have of patients who are dissatisfied in some way with their GP service. In addition, other factors such as departmental 'culture' and the separation that exists between hospital and community health professionals may have an important influence. The effect such negative perceptions have on the relationship between A&E departments and general practitioners, and the quality of care provided to patients attending A&W with primary care problems are discussed.


Glucocorticoids and non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the global obesity and metabolic disease epidemic and is rapidly becoming the leading cause of liver cirrhosis and indication for liver transplantation worldwide. The hallmark pathological finding in NAFLD is excess lipid accumulation within hepatocytes, but it is a spectrum of disease ranging from benign hepatic steatosis to steatohepatitis through to fibrosis, cirrhosis and risk of hepatocellular carcinoma. The exact pathophysiology remains unclear with a multi-hit hypothesis generally accepted as being required for inflammation and fibrosis to develop after initial steatosis. Glucocorticoids have been implicated in the pathogenesis of NAFLD across all stages. They have a diverse array of metabolic functions that have the potential to drive NAFLD acting on both liver and adipose tissue. In the fasting state, they are able to mobilize lipid, increasing fatty acid delivery and in the fed state can promote lipid accumulation. Their action is controlled at multiple levels and in this review will outline the evidence base for the role of GCs in the pathogenesis of NAFLD from cell systems, rodent models and clinical studies and describe interventional strategies that have been employed to modulate glucocorticoid action as a potential therapeutic strategy.


Opt-out provider-initiated HIV testing and counselling in primary care outpatient clinics in Zambia.
To increase case-finding of infection with human immunodeficiency virus (HIV) in Zambia and their referral to HIV care and treatment by supplementing existing client-initiated voluntary counselling and testing (VCT), the dominant mode of HIV testing in the country. Lay counsellors offered provider-initiated HIV testing and counselling (PITC) to all outpatients who attended primary clinics and did not know their HIV serostatus. Data on counselling and testing were collected in registers. Outcomes of interest included HIV testing coverage, the acceptability of testing, the proportion testing HIV-positive (HIV+), the proportion enrolling in HIV care and treatment and the time between testing and enrolment. After the addition of PITC to VCT, the number tested for HIV infection in the nine clinics was twice the number undergoing VCT alone. Over 30 months, 44,420 patients were counselled under PITC and 31,197 patients, 44% of them men, accepted testing. Of those tested, 21% (6572) were HIV+; 38% of these HIV+ patients (2515) enrolled in HIV care and treatment. The median time between testing and enrolment was 6 days. The acceptability of testing rose over time. The introduction of routine PITC using lay counsellors into health-care clinics in Lusaka, Zambia, dramatically increased the uptake and acceptability of HIV testing. Moreover, PITC was incorporated rapidly into primary care outpatient departments. Maximizing the number of patients who proceed to HIV care and treatment remains a challenge and warrants further research.


Adsorption of a carboxylic acid-functionalized aminoxyl radical onto SiO₂.
Silicon wafers both without and with silicon(IV) oxide surface coverage were covered with benzene solutions of stable organic radical 3-(N-tert-butyl-N-aminoxyl)benzoic acid (mNBA). X-ray photoelectron spectroscopy supported the presence of the radical on both surface-cleaned (oxide-reduced) and oxide-covered surfaces. Optical waveguide spectroscopy showed that the radical retained its structure while adsorbed to the surface of the wafers, without noticeable decomposition. AFM and MFM imaging showed that the radical formed blocky particles with a change in rms roughness from 0.3 nm premodification to 1.7 nm postmodification on the surface-cleaned silicon. Similar experiments using oxide-coated silicon showed that the radical adsorbed to form much smoother layers, with a small change in rms roughness from 0.2 to 0.3 nm. Contact angle measurements of water on the premodified and postmodified samples showed a large, hydrophobic change in the silicon oxide surface but only a modest change in the surface-cleaned silicon surface. Samples of mNBA adsorbed onto silica gel showed strong electron-spin resonance signals from the aminoxyl spin, even years after production. The results demonstrate the prospects for treating and coating oxide-covered silicon wafers and silicon oxide-coated particles with a paramagnetically active organic substrate, without major chemical modification of the pretreatment surface; the resulting organic spin sites can be stable for years.


Action monitoring in children with or without a family history of ADHD--effects of gender on an endophenotype parameter.
Attention-deficit/hyperactivity disorder (ADHD) is a frequent and highly heritable disorder overrepresented in boys. In a recent study investigating boys only, we found that action monitoring deficits as reflected by certain behavioral and electrophysiological parameters were familially driven. As gender may also have an important impact, this was examined in the current study with nonaffected children aged 8-15 years having relatives suffering from ADHD (N=37, 21 female symbol) and with age-matched controls without family history of ADHD (N=33, 11 female symbol). Extending our previous findings that action monitoring is a potential endophenotype for boys with ADHD, familially driven deficits were confirmed independently of gender. Thus, despite sharing the phenotype with controls, nonaffected siblings showed ADHD-like impairments albeit of smaller magnitude. However, girls performed generally more accurately, which in turn may have produced the differences between nonaffected siblings and controls in affective error processing that were not present in our boys-only assessment.


Phylogenetic analysis and geographical distribution of Theileria equi and Babesia caballi sequences from horses residing in Spain.
The intraerythrocytic protozoans Theileria equi and Babesia caballi are the causative agents of equine piroplasmosis (EP), one of the most important equine tick-borne diseases due to its significant impact on global international horse trade. Although EP is known to be endemic in Spain, previous phylogenetic studies have only been conducted for limited geographical regions. Therefore, the objective of this study was to evaluate the genetic diversity and distribution of these parasite species nationwide. This was performed by amplification of the 18S small subunit (SSU) rRNA gene from 100 EP positive equine blood samples using a nested PCR protocol, and sequencing the obtained amplicons. Seventy-seven T. equi and six B. caballi isolates were successfully sequenced and phylogenetic analysis revealed that the T. equi isolates grouped into the previously described clades A (n = 21/77), D (n = 1/77) and E (n = 55/77), while B. caballi isolates were placed into clades A (n = 5/6) and B (n = 1/6). Isolates from T. equi clade D and B. caballi clade B have not previously been reported in Spain. A greater intra-clade diversity (97.3-98.3 % identity) was observed between T. equi clade E isolates compared to those within clade A (99.7-100 % identity). Additionally, a multivariable logistic regression model was used to analyse associations between the clade of T. equi infection and available epidemiological data. Horses residing in Spanish northern regions were statistically more likely to be infected with T. equi clade E (p = 0.01). We conclude that while extensive sequence variation of equine piroplasms exists in Spanish infected horses, a requirement for increased equine movement controls between Spain and EP-endemic countries should be considered.


Fecal human β-defensin-2 (hBD-2) levels and gut microbiota patterns in preterm neonates with different feeding patterns.
Human β-defensin-2 (hBD-2) is an essential antibacterial peptide involved in innate immunity and is expressed in breast milk and intestinal mucosa. The aim of this study was to investigate fecal hBD-2 levels and gut microbiota in preterm neonates with different feeding patterns. This study was cross-sectionally designed and included 44 preterm neonates categorized into four groups as follows: breast milk only, breast milk predominant, formula milk predominant, formula milk only. The study was conducted at the Neonatology Ward, National Center Hospital Cipto Mangunkusumo, Jakarta from November 2016 to April 2017. hBD-2 levels were measured by ELISA. Intestinal bacteria were quantified by qPCR. hBD-2 levels were significantly different between groups (one-way ANOVA, p=0.004) and the highest value of hBD-2 was found in the formula milk predominant group (344.87±61.2 ng/mL). hBD-2 levels were positively correlated with feeding pattern (Spearman correlation test, p=0.009, r=0.391). There were no significant differences in the total number of specific intestinal microbiota (Bifidobacterium, Lactobacillus and Klebsiella) among groups (one-way ANOVA, p>0.05). Interestingly, the formula milk only group had the highest amount of Klebsiella compared with other groups. hBD-2 levels were not correlated with the quantity of Bifidobacterium, Lactobacillus and Klebsiella (Pearson correlation test, p>0.05). hBD-2 levels were significantly higher in the formula milk predominant group compared with the breast milk only group. Gut microbiota patterns showed that Bifidobacterium and Lactobacillus were higher in the breast milk only group, while Klebsiella was higher in formula milk group, although this difference was not statistically significant.


Improvement of Predictive Ability by Uniform Coverage of the Target Genetic Space.
Genome-enabled prediction provides breeders with the means to increase the number of genotypes that can be evaluated for selection. One of the major challenges in genome-enabled prediction is how to construct a training set of genotypes from a calibration set that represents the target population of genotypes, where the calibration set is composed of a training and validation set. A random sampling protocol of genotypes from the calibration set will lead to low quality coverage of the total genetic space by the training set when the calibration set contains population structure. As a consequence, predictive ability will be affected negatively, because some parts of the genotypic diversity in the target population will be under-represented in the training set, whereas other parts will be over-represented. Therefore, we propose a training set construction method that uniformly samples the genetic space spanned by the target population of genotypes, thereby increasing predictive ability. To evaluate our method, we constructed training sets alongside with the identification of corresponding genomic prediction models for four genotype panels that differed in the amount of population structure they contained (maize Flint, maize Dent, wheat, and rice). Training sets were constructed using uniform sampling, stratified-uniform sampling, stratified sampling and random sampling. We compared these methods with a method that maximizes the generalized coefficient of determination (CD). Several training set sizes were considered. We investigated four genomic prediction models: multi-locus QTL models, GBLUP models, combinations of QTL and GBLUPs, and Reproducing Kernel Hilbert Space (RKHS) models. For the maize and wheat panels, construction of the training set under uniform sampling led to a larger predictive ability than under stratified and random sampling. The results of our methods were similar to those of the CD method. For the rice panel, all training set construction methods led to similar predictive ability, a reflection of the very strong population structure in this panel.


Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection.
To better understand the basis for human immunodeficiency virus type 1 (HIV-1) persistence and latency, the form in which viral DNA exists in the peripheral T lymphocyte reservoir of infected individuals was investigated. In asymptomatic individuals, HIV-1 was harbored predominantly as full-length, unintegrated complementary DNA. These extrachromosomal DNA forms retained the ability to integrate upon T cell activation in vitro. In patients with acquired immunodeficiency syndrome (AIDS), there was an increase in integrated relative to extrachromosomal DNA forms. By analysis of DNA from patient lymphocyte subpopulations depleted of human lymphocyte antigen-Dr receptor-positive cells, quiescent T cells were identified as the source of extrachromosomal HIV-1 DNA. Thus quiescent T lymphocytes may be a major and inducible HIV-1 reservoir in infected individuals.


When genetics and genealogies tell different stories-maternal lineages in Gaspesia.
Data from uniparentally inherited genetic systems were used to trace evolution of human populations. Reconstruction of the past primarily relies on variation in present-day populations, limiting historical inference to lineages that are found among living subjects. Our analysis of four population groups in the Gaspé Peninsula, demonstrates how this may occasionally lead to erroneous interpretations. Mitochondrial DNA analysis of Gaspesians revealed an important admixture with Native Americans. The most likely scenario links this admixture to French-Canadians from the St. Lawrence Valley who moved to Gaspesia in the 19th century. However, in contrast to genetic data, analysis of genealogical record shows that Native American maternal lineages were brought to Gaspesia in the 18th century by Acadians who settled on the south-western coast of the peninsula. Intriguingly, within three generations, virtually all Métis Acadian families separated from their nonadmixed relatives and moved eastward mixing in with other Gaspesian groups, in which Native American maternal lines are present in relatively high frequencies. Over time, the carriers of these lines eventually lost memory of their mixed Amerindian-Acadian origin. Our results show that a reliable reconstruction of population history requires cross-verification of different data sources for consistency, thus favouring multidisciplinary approaches.


Vuvuzelas at South African soccer matches: risks for spectators' hearing.
South African Premier Soccer League (PSL) matches are known worldwide as some of the noisiest recreational events. Therefore, the objectives of this study were to i) measure noise levels during different PSL matches; ii) measure changes in auditory function after attending PSL matches; and iii) determine the factors that increase the risk of overexposure to noise during PSL matches. The study used a descriptive quantitative analytical pre- and post-exposure design. Participants (n = 19, and n = 10) attended two PSL matches. Each participant's auditory function was assessed using distortion product oto-acoustic emissions (DPOAEs) before and after attending a PSL match. Peak and equivalent continuous noise levels as well as noise dose were measured during each match. Noise levels recorded during the poorly attended Match 1 were lesser than those of the well-attended Match 2. Participants attending Match 2 had statistically significant reduction in their DPOAE amplitudes after the match (P = 0.003) than those attending Match 1. Vuvuzela blowers and participants seated within 1 m from them were most at risk of harm to their hearing with significant reduction in DPOAE amplitudes post the match (P = 0.002 and P = 0.008, respectively). It was therefore concluded that noise levels at well-attended South African PSL matches pose a significant risk to spectators' auditory function as shown by reduced DPOAE amplitude post match attendance. Three risk factors for overexposure to noise during the match were identified: blowing the vuvuzela, close proximity to the individual blowing the vuvuzela as well as spectator turnout at the match.


Myosin step size. Estimation from slow sliding movement of actin over low densities of heavy meromyosin.
We have estimated the step size of the myosin cross-bridge (d, displacement of an actin filament per one ATP hydrolysis) in an in vitro motility assay system by measuring the velocity of slowly moving actin filaments over low densities of heavy meromyosin on a nitrocellulose surface. In previous studies, only filaments greater than a minimum length were observed to undergo continuous sliding movement. These filaments moved at the maximum speed (Vo), while shorter filaments dissociated from the surface. We have now modified the assay system by including 0.8% methylcellulose in the ATP solution. Under these conditions, filaments shorter than the previous minimum length move, but significantly slower than Vo, as they are propelled by a limited number of myosin heads. These data are consistent with a model that predicts that the sliding velocity (v) of slowly moving filaments is determined by the product of vo and the fraction of time when at least one myosin head is propelling the filament, that is, v = vo [1-(1-ts/tc)N], where ts is the time the head is strongly bound to actin, tc is the cycle time of ATP hydrolysis, and N is the average number of myosin heads that can interact with the filament. Using this equation, the optimum value of ts/tc to fit the measured relationship between v and N was calculated to be 0.050. Assuming d = vots, the step size was then calculated to be between 10nm and 28 nm per ATP hydrolyzed, the latter value representing the upper limit. This range is within that of geometric constraint for conformational change imposed by the size of the myosin head, and therefore is not inconsistent with the swinging cross-bridge model tightly coupled with ATP hydrolysis.


Yield Reduction and Root Damage to Cotton Induced by Belonolaimus longicaudatus.
Sting nematode (Belonolaimus longicaudatus) is recognized as a pathogen of cotton (Gossypium hirsutum), but the expected damage from a given population density of this nematode has not been determined. The objective of this study was to quantify the effects of increasing initial population densities (Pi) of B. longicaudatus on cotton yield and root mass. In a field plot study, nematicide application and cropping history were used to obtain a wide range of Pi values. Cotton yields were regressed on Pi density of B. longicaudatus to quantify yield losses in the field. In controlled environmental chambers, cotton was grown in soil infested with increasing Pi's of B. longicaudatus. After 40 days, root systems were collected, scanned on a desktop scanner, and root lengths were measured. Root lengths were regressed on inoculation density of B. longicaudatus to quantify reductions in the root systems. In the field, high Pi's (>100 nematodes/130 cm(3) of soil) reduced yields to near zero. In controlled environmental chamber studies, as few as 10 B. longicaudatus/130 cm(3) of soil caused a 39% reduction in fine cotton roots, and 60 B. longicaudatus/130 cm(3) of soil caused a 70% reduction. These results suggest that B. longicaudatus can cause significant damage to cotton at low population densities, whereas at higher densities crop failure can result.


Physiological 3D tissue model of the airway wall and mucosa.
This protocol describes the setup, maintenance and characteristics of a tissue-engineered model of the human bronchial mucosa that can be used for basic physiology and pathophysiology studies. The model includes a well-differentiated epithelium with functional cilia, mucus secretion and subepithelial fibroblasts within type I collagen. The tissue is created within porous polymeric wells to prevent gel contraction and allow culture at the air-liquid interface. It requires at least 2 wk to be established and can be maintained thereafter for over 4 wk, with tissue differentiation moving towards a more physiologically relevant phenotype with increasing time in culture. Over time, the extracellular matrix also remodels, depositing proteins such as types III and IV collagen and fibronectin. Because it recapitulates many key anatomical and functional features of the airway wall, this model is well suited for a wide range of studies, including those on airway remodeling, transepithelial transport and inflammatory cell interactions with the mucosa. The entire protocol takes 4-6 wk, including cell expansion, depending on the extent of ciliogenesis desired.


Selective impairment of acetylcholine-mediated endothelium-dependent relaxation in isolated resistance arteries of the streptozotocin-induced diabetic rat.
1. There is growing evidence that an impairment in the function of nitric oxide synthase may play a role in the vascular complications of diabetes mellitus. The relaxation of resistance arteries from the mesenteric and hindlimb circulations of streptozotocin-induced diabetic rats and age-matched controls were investigated using two endothelium-dependent vasodilators, bradykinin and acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. The contractile responses to the alpha 1-adrenergic agonist phenylephrine were also studied. 2. Endothelium-dependent relaxation to acetylcholine was impaired in the diabetic rats in arteries from both mesenteric and hindlimb circulations (hindlimb pEC50, 7.93 +/- 0.08 in the control compared with 7.38 +/- 0.10 in the diabetic rat; mesenteric pEC50, 7.47 +/- 0.04 in the control compared with 6.65 +/- 0.06 in the diabetic rat; unpaired t-test P < 0.0001). Bradykinin elicited relaxation in only the mesenteric arteries, and this was not attenuated in the diabetic rats compared with controls. 3. Endothelium-independent relaxation to sodium nitroprusside was similar in the two circulations and was not abnormal in the diabetic rats. There was no significant difference in constrictor responses to phenylephrine between diabetic rats and controls in either the hindlimb or mesenteric arteries, in contrast to an earlier study in which we showed increased sensitivity to noradrenaline. 4. The diabetic rats therefore demonstrated a specific impairment of receptor-mediated endothelium-dependent relaxation to acetylcholine. These results suggest that, in this diabetic model, the ability of the endothelium to relax arteries via nitric oxide may involve a defect of a specific signal transduction pathway, leading to reduced production of nitric oxide.


Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders.
Impaired 5-HT3 receptor function is likely involved in the pathogenesis of functional gastrointestinal disorders (FGID) and 5-HT3 receptor antagonists are effective treatments for chemotherapy-induced nausea and vomiting (CINV) and irritable bowel syndrome (IBS). The monoterpene alcohol menthol and the aporphine alkaloid boldine combat symptoms of gastrointestinal diseases; both interact with other members of the Cys-loop ligand-gated ion channel family and may therefore also act on 5-HT3 receptors. The impact of boldine and menthol on human recombinant homomeric 5-HT3 A- and heteromeric 5-HT3 AB receptors in HEK293 cells was determined by radioligand binding, a luminescence-based Ca(2+) assay, and a membrane potential assay. 5-HT3 protein and mRNA expression was assessed in human colon tissue. Boldine and menthol inhibited the 5-HT-induced activation of 5-HT3 receptors in the low and middle micromolar range, respectively. Boldine was a competitive antagonist of both receptors being 6.5- to 10-fold more potent at 5-HT3 A- vs 5-HT3 AB receptors. Menthol non-competitively and stereoselectively inhibited both receptors: In contrast to (+)-menthol, (-)-menthol was significantly more potent toward 5-HT3 A- vs 5-HT3 AB receptors. We show co-expression of 5-HT3A and 5-HT3B subunits in the human gut epithelium, the lamina propria, the myenteric plexus, and the muscular cell layer. The demonstrated 5-HT3 inhibitory effects may be relevant for boldine's and menthol's alleviating properties on FGID and may encourage clinical studies with the compounds or the plant extracts for CINV and IBS treatment. The found receptor-discriminative properties make boldine and (-)-menthol to potentially useful tools for analyzing structural differences between these receptor subtypes.


A retinoic acid-inducible transgenic marker of sino-atrial development in the mouse heart.
To study the specification of inflow structures in the heart we generated transgenic animals harboring the human alkaline phosphatase (HAP) gene driven by the proximal 840 bp of a quail SMyHC3 promoter. In transgenic mice, the SMyHC3-HAP reporter was expressed in posterior heart precursors at 8.25 dpc, in sinus venosa and in the atrium at 8.5 and 9.0 dpc, and in the atria from 10.5 dpc onwards. SMyHC3-HAP transgene expression overlapped synthesis and endogenous response to retinoic acid (RA) in the heart, as determined by antibodies directed against a key RA synthetic enzyme and by staining of RAREhsplacZ transgenic animals. A single pulse of all-trans RA administered to pregnant mice at 7.5, but not after 8.5, dpc induced cardiac dismorphology, ranging from complete absence of outflow tract and ventricles to hearts with reduced ventricles expressing both SMyHC3-HAP and ventricular markers. Blockade of RA synthesis with disulfiram inhibited RA-induced transcription and produced hearts lacking the atrial chamber. This study defines a novel marker for atrial-restricted transcription in the developing mouse heart. It also suggests that atrial-specific gene expression is controlled by localized synthesis of RA, and that exclusion of RA from ventricular precursors is essential for correct specification of the ventricles.


Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma.
The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease-free survival (P=0.0235). PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage, tall cell variant histological subtype, and a poor disease-free survival (P=0.0005, P=0.0006, P=0.0398, P=0.0004, P=0.0111, P=0.0003, and P=0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of XIAP (P<0.0001) and Bcl-XL (P<0.0001). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3' kinase (PI3K)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor disease-free survival.


EAES ductal stone study. Preliminary findings of multi-center prospective randomized trial comparing two-stage vs single-stage management.
The current management of patients with ductal calculi and gallstone disease consists of endoscopic stone extraction (ESE) followed by laparoscopic cholecystectomy (LC). The advent of techniques of laparoscopic ductal stone clearance has introduced an alternative single stage laparoscopic treatment for these patients. The EAES ductal stone trial was set up to compare the relative efficacy and outcome of these two management options. The study consists of a prospective randomized controlled clinical trial comparing two management options of patients undergoing LC and suspected of harbouring common duct stones. Patients registered into the trial are randomized to one of two arms: (i) Group A-preoperative ERC with ESE followed by LC during the same hospital admission. (ii) Group B-single stage laparoscopic management consisting of LC and laparoscopic stone extraction either by the trans-cystic duct route or by direct supraduodenal common duct exploration. This preliminary analysis was carried out on 207 randomized patients with comparisons being made on the intention to treat principle. The two groups (A = 106, B = 101) were comparable with respect to clinical features. ASA grade, serum biochemistry and ultrasound findings. These preliminary findings indicate equivalent success rates and patient morbidity between the two management options but a shorter hospital stay (cost benefit) with the single stage laparoscopic treatment. Trans-cystic duct extraction is a more benign procedure than laparoscopic supraduodenal CBD exploration and is accompanied by a significantly shorter hospital stay. The higher incidence of conversion in the single stage laparoscopic group compared to the two-stage arm is due to the preference for open common duct exploration when the laparoscopic attempt failed by the majority of participating surgeons. The results to-date suggest that in fit patients, single stage laparoscopic treatment is the better option and the role of ESE should change to selective use in those patients in whom laparoscopic ductal stone extraction has failed.


A novel method for measurement of submembrane ATP concentration.
There has been considerable debate as to whether adenosine triphosphate (ATP) is compartmentalized within cells and, in particular, whether the ATP concentration directly beneath the plasma membrane, experienced by membrane proteins, is the same as that of the bulk cytoplasm. This issue has been difficult to address because there is no indicator of cytosolic ATP, such as those available for Ca(2+), capable of resolving the submembrane ATP concentration ([ATP](sm)) in real time within a single cell. We show here that mutant ATP-sensitive K(+) channels can be used to measure [ATP](sm) by comparing the increase in current amplitude on patch excision with the ATP dose-response curve. In Xenopus oocytes, [ATP](sm) was 4.6 +/- 0.3 mm (n = 29) under resting conditions, slightly higher than that measured for the bulk cytoplasm (2.3 mm). In mammalian (COSm6) cells, [ATP](sm) was slightly lower and averaged 1.4 +/- 0.1 mm (n = 66). Metabolic poisoning (10 min of 3 mm azide) produced a significant fall in [ATP](sm) in both types of cells: to 1.2 +/- 0.1 mm (n = 24) in oocytes and 0.8 +/- 0.11 mm for COSm6 cells. We conclude that [ATP](sm) lies in the low millimolar range and that there is no gradient between bulk cytosolic and submembrane [ATP].


Follow the nevus: the cost-utility of monitoring for growth of choroidal nevi.
To develop a model to evaluate the cost-utility of choroidal nevi monitoring recommendations with varying clinical risk factors. A Markov model was created to evaluate the cost-utility in cost per quality-adjusted life-year ($/QALY) for monitoring patients with choroidal nevus. This probabilistic model was applied both to a hypothetically monitored and unmonitored group of patients beginning at different ages and with varying clinical risk factors of the nevus. Duration of screening was modeled for the remainder of the patients' life expectancy. Best available clinical data on the prevalence and incidence of choroidal nevi/melanoma, and relative risk of nevus transformation were combined with the initial and downstream costs of screening, downstream costs of melanoma-related mortality, and QALY saved by monitoring, to estimate the best monitoring regimen. Main outcome measures were average $/QALY saved by consensus recommended monitoring scenarios for the duration of a patient's remaining life expectancy in comparison with no follow-up, and the cost-utility of modified regimens. The $/QALY of the recommended monitoring scenarios varied substantially based on nevus clinical risk factors, patient age, frequency of follow-up, and objective testing utilized. The $/QALY for the recommended monitoring scenario of a flat nevus without risk factors in a 60-year-old patient was $77 180. The $/QALY for monitoring a nevus with 3 clinical risk factors in a 60-year-old patient was $85 393. The $/QALY values for differently-aged patients were larger, and intermediate degrees of risk factors for nevus growth varied, depending largely upon the specifics of the modeled monitoring scenarios. The average $/QALY of currently recommended monitoring scenarios fall within economically acceptable standards and could provide insight for formulating appropriate clinical strategies. Cost-utility could be enhanced by targeting higher risk groups and considering less frequent monitoring for the lower risk groups.


Anesthetic approach to high-risk patients and prolonged awake craniotomy using dexmedetomidine and scalp block.
Awake craniotomy with intraoperative speech or motor testing is relatively contraindicated in cases requiring prolonged operative times and in patients with severe medical comorbidities including anxiety, anticipated difficult airway, obesity, large tumors, and intracranial hypertension. The anesthetic management of neurosurgical patients who possess these contraindications but would be optimally treated by an awake procedure remains unclear. We describe a new anesthetic approach for awake craniotomy that did not require any airway manipulation, utilizing a bupivacaine-based scalp nerve block, and dexmedetomidine as the primary hypnotic-sedative agent. Using this technique, we provided optimal operative conditions to perform awake craniotomy facilitating safe tumor resection, while utilizing intraoperative electrocorticography for motor and speech mapping in a cohort of 10 patients at a high risk for airway compromise and complications associated with patient comorbidities. All patients underwent successful awake craniotomy, intraoperative mapping, and tumor resection with adequate sedation for up to 9 hours (median 3.5 h, range 3 to 9 h) without any loss of neurological function, airway competency, or the need to provide any active rescue airway management. We report 4 of these cases that highlight our experience: 1 case required prolonged surgery because of the complexity of tumor resection and 3 patients had important medical comorbidities and/or relative contraindication for an awake procedure. Dexmedetomidine, with concurrent scalp block, is an effective and safe anesthetic approach for awake craniotomy. Dexmedetomidine facilitates the extension procedure complexity and duration in patients who might traditionally not be considered to be candidates for this procedure.


Taro flour (Colocasia esculenta) increases testosterone levels and gametogenic epithelium of Wistar rats.
This study evaluated the effects of diet containing taro flour on hormone levels and the seminiferous tubules morphology of rats. After weaning, the male rats were divided into two groups (n=12 each): control group (CG) treated with control diet and taro group (TG), fed with 25% taro flour for 90 days. Food, caloric intake, mass and body length were evaluated at experiment end. Testis followed the standard histological processing. Immunostaining was performed using an anti-vimentin antibody to identify Sertoli cells. In histomorphometry, total diameter, total area, epithelial height, luminal height and luminal area were analyzed. The testosterone levels were performed using the radioimmunoassay method. Group TG presented (P<0.05): increase in mass, body length, testicular weight, histomorphometric parameters and hormonal levels. Food intake, calorie and Sertoli cells not presented statistical differences. The taro promoted increase in the testicles parameters and hormones.


Asthma attacks and deprivation: gradients in use of mobile emergency medical services.
To test whether rates of emergency telephone calls for asthma attacks are associated with contextual socioeconomic deprivation in the Strasbourg metropolitan area (France). Two mobile emergency medical service networks provided all data for 2000-2005 about emergency calls for asthma attacks, georeferenced by census block. Contextual deprivation was measured for each census block by a composite index, constructed by principal component analysis. Emergency call rates were calculated for each census block and for different age groups. Empirical Bayesian smoothing was used to reduce the instability of outlying rates. Positive spatial autocorrelation was detected in both the health and the socioeconomic datasets. In all age groups, rates of calls for asthma attacks increased linearly with deprivation. Correlation coefficients between these two factors varied according to age group: 0.53 for the group aged 0-9 years, 0.46 for 10-19 years, 0.65 for 20-39 years, 0.70 for 40-64 years, 0.68 for 65 and older, and 0.77 for the age-standardised incidence ratio. These correlation coefficients were highly significant (p<0.01), even after spatial autocorrelation was taken into account. The socioeconomic gradients observed are consistent with those observed for severe forms of asthma and asthma hospitalisations in Western countries.


Recovery from acute injury: clinical, methodological and philosophical considerations.
The foundational basis for rehabilitation of musculoskeletal injury as a profession rests upon the ability of an organism to recover from a deviation in homeostasis, and the clinician's ability to influence that process. Much work has been done in an effort to describe and predict recovery from acute injury, in particular soft tissue injuries of the spine (whiplash and low back pain). Recent reviews have identified inconsistencies in the criteria for identifying recovery in this literature that hamper attempts at knowledge translation. This article is intended to stimulate discussion around a new, standardised and acceptable set of criteria for discriminating between the injured individual who reaches a satisfying end to the experience of injury and the individual who does not reach that end. Self-discrepancy theory and self-determination theory are used to frame the discussion. It is hoped that the introduction of a new paradigm will lead to the development of more standardised, acceptable and useful outcomes, and will facilitate data synthesis from studies on prognosis and intervention for acute musculoskeletal injury.


Evaluating the relative contributions of copying and reconstruction processes in cultural transmission episodes.
The ability to transmit information between individuals through social learning is a foundational component of cultural evolution. However, how this transmission occurs is still debated. On the one hand, the copying account draws parallels with biological mechanisms for genetic inheritance, arguing that learners copy what they observe and novel variations occur through random copying errors. On the other hand, the reconstruction account claims that, rather than directly copying behaviour, learners reconstruct the information that they believe to be most relevant on the basis of pragmatic inference, environmental and contextual cues. Distinguishing these two accounts empirically is difficult based on data from typical transmission chain studies because the predictions they generate frequently overlap. In this study we present a methodological approach that generates different predictions of these accounts by manipulating the task context between model and learner in a transmission episode. We then report an empirical proof-of-concept that applies this approach. The results show that, when a model introduces context-dependent embedded signals to their actions that are not intended to be transmitted, it is possible to empirically distinguish between competing predictions made by these two accounts. Our approach can therefore serve to understand the underlying cognitive mechanisms at play in cultural transmission and can make important contributions to the debate between preservative and reconstructive schools of thought.


Acute Orthotic Intervention Does Not Affect Muscular Response Times and Activation Patterns at the Knee.
OBJECTIVE: To evaluate the short-term effect of a semirigid foot orthotic device on response times and activation patterns of knee musculature in individuals with hyperpronation after a lower extremity perturbation in a single-leg, weight-bearing stance. DESIGN AND SETTING: We used a lower extremity perturbation device designed to produce a forward and either internal or external rotation of the trunk and femur on the weight-bearing tibia to evoke a reflex response. Subjects were tested both with and without orthotic devices. SUBJECTS: Seventeen (13 male, 4 female) volunteers (age, 20.6 +/- 1.8 years; height, 181.0 +/- 8.1 cm; weight, 87.4 +/- 19.5 kg; navicular drop, 12.1 +/- 1.8 mm) with a navicular drop greater than 10 mm volunteered for this study. MEASUREMENTS: Long latency reflex times were recorded via surface electromyography for the medial and lateral hamstrings, gastrocnemius, and quadriceps muscles. RESULTS: A dependent-sample t test revealed a significant decrease in navicular drop with orthotic intervention (P <.0001). With that confirmed, separate repeated-measures analyses of variance with 2 within factors (orthotic condition and muscle) revealed no significant difference in muscle response time between orthotic and nonorthotic conditions for either internal or external rotation perturbation. Although we found a main effect for muscle for both internal (P <.0001) and external (P <.0001) rotation, indicating a preferred muscle activation order, this activation order did not differ between orthotic and nonorthotic conditions (internal rotation P =.674, external rotation P =.829). CONCLUSIONS: Our findings suggest that a short-term application of a semirigid orthotic device does not alter muscle response times or activation patterns of the muscles that stabilize the knee. Further research is needed to determine whether changes in activation patterns may occur over time since mechanical adaptations occur with long-term wear.


Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures.
Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve the functionality of the DNA tag severely restricts the choice of chemical methods for library synthesis. Acidic organocatalysts, transition metals, and oxidants furnish diverse drug-like structures from simple starting materials, but cause loss of genetic information by depurination. A hexathymidine oligonucleotide, called "hexT" allows the chemist utilizing these classes of catalysts to access a potentially broad variety of structures in the initial step of library synthesis. We exploited its catalyst tolerance to efficiently synthesize diverse substituted β-carbolines, pyrazolines, and pyrazoles from readily available starting materials as hexT conjugates by acid- and Au(i)-catalysis, respectively. The hexT conjugates were ligated to coding DNA sequences yielding encoded screening libraries inspired by drug structures.


The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial.
Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma. Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40 mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6 months (PFR(6 months)). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P(0) = 50%; P(1) = 70%; α = 0.05; β = 0.10). Thirty patients were enrolled. PFR(6 months) was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6 months and median OS was 6 and 8 months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm. In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended.


Antarctic krill 454 pyrosequencing reveals chaperone and stress transcriptome.
The Antarctic krill Euphausia superba is a keystone species in the Antarctic food chain. Not only is it a significant grazer of phytoplankton, but it is also a major food item for charismatic megafauna such as whales and seals and an important Southern Ocean fisheries crop. Ecological data suggest that this species is being affected by climate change and this will have considerable consequences for the balance of the Southern Ocean ecosystem. Hence, understanding how this organism functions is a priority area and will provide fundamental data for life history studies, energy budget calculations and food web models. The assembly of the 454 transcriptome of E. superba resulted in 22,177 contigs with an average size of 492bp (ranging between 137 and 8515bp). In depth analysis of the data revealed an extensive catalogue of the cellular chaperone systems and the major antioxidant proteins. Full length sequences were characterised for the chaperones HSP70, HSP90 and the super-oxide dismutase antioxidants, with the discovery of potentially novel duplications of these genes. The sequence data contained 41,470 microsatellites and 17,776 Single Nucleotide Polymorphisms (SNPs/INDELS), providing a resource for population and also gene function studies. This paper details the first 454 generated data for a pelagic Antarctic species or any pelagic crustacean globally. The classical "stress proteins", such as HSP70, HSP90, ferritin and GST were all highly expressed. These genes were shown to be over expressed in the transcriptomes of Antarctic notothenioid fish and hypothesized as adaptations to living in the cold, with the associated problems of decreased protein folding efficiency and increased vulnerability to damage by reactive oxygen species. Hence, these data will provide a major resource for future physiological work on krill, but in particular a suite of "stress" genes for studies understanding marine ectotherms' capacities to cope with environmental change.


Systemic nocardiosis in a splenectomized patient with systemic lupus erythematosus: successful treatment using linezolid.
A splenectomized patient with systemic lupus erythematosus, who had previously been treated with high doses of corticosteroids, presented with headaches and symptoms of a respiratory tract infection. A magnetic resonance imaging scan of the brain revealed a ring-enhancing lesion, and Nocardia asteroides was isolated from a stereotactic biopsy specimen. After adverse reactions to a number of antibiotics, infection control was finally achieved by the new oxazolidinone drug, linezolid. Nocardiosis should be considered as a differential diagnosis in all immunocompromised patients who develop an obscure infection; delay in diagnosis and subsequent initiation of appropriate treatment often results in a fatal outcome. Linezolid is a new option for the treatment of nocardiosis and is effective when given orally.


Mapping leaf surface landscapes.
Leaf surfaces provide the ecologically relevant landscapes to those organisms that encounter or colonize the leaf surface. Leaf surface topography directly affects microhabitat availability for colonizing microbes, microhabitat quality and acceptability for insects, and the efficacy of agricultural spray applications. Prior detailed mechanistic studies that examined particular fungi-plant and pollinator-plant interactions have demonstrated the importance of plant surface topography or roughness in determining the outcome of the interactions. Until now, however, it has not been possible to measure accurately the topography--i.e., the three-dimensional structure--of such leaf surfaces or to record precise changes in patterns of leaf surface elevation over time. Using contact mode atomic force microscopy, we measured three-dimensional coordinates of upper leaf surfaces of Vaccinium macrocarpon (cranberry), a perennial plant, on leaves of two age classes. We then produced topographic maps of these leaf surfaces, which revealed striking differences between age classes of leaves: old leaves have much rougher surfaces than those of young leaves. Atomic force microscope measurements were analyzed by lag (1) autocorrelation estimates of leaf surfaces by age class. We suggest that the changes in topography result from removal of epicuticular lipids and that the changes in leaf surface topography influence phylloplane ecology. Visualizing and mapping leaf surfaces permit detailed investigations into leaf surface-mediated phenomena, improving our understanding of phylloplane interactions.


Euthanasia embedded in palliative care. Responses to essentialistic criticisms of the Belgian model of integral end-of-life care.
The Belgian model of 'integral' end-of-life care consists of universal access to palliative care (PC) and legally regulated euthanasia. As a first worldwide, the Flemish PC organisation has embedded euthanasia in its practice. However, some critics have declared the Belgian-model concepts of 'integral PC' and 'palliative futility' to fundamentally contradict the essence of PC. This article analyses the various essentialistic arguments for the incompatibility of euthanasia and PC. The empirical evidence from the euthanasia-permissive Benelux countries shows that since legalisation, carefulness (of decision making) at the end of life has improved and there have been no significant adverse 'slippery slope' effects. It is problematic that some critics disregard the empirical evidence as epistemologically irrelevant in a normative ethical debate. Next, rejecting euthanasia because its prevention was a founding principle of PC ignores historical developments. Further, critics' ethical positions depart from the PC tenet of patient centeredness by prioritising caregivers' values over patients' values. Also, many critics' canonical adherence to the WHO definition of PC, which has intention as the ethical criterion is objectionable. A rejection of the Belgian model on doctrinal grounds also has nefarious practical consequences such as the marginalisation of PC in euthanasia-permissive countries, the continuation of clandestine practices and problematic palliative sedation until death. In conclusion, major flaws of essentialistic arguments against the Belgian model include the disregard of empirical evidence, appeals to canonical and questionable definitions, prioritisation of caregiver perspectives over those of patients and rejection of a plurality of respectable views on decision making at the end of life.


The different roles of molecular classification according to upfront autologous stem cell transplantation in advanced-stage diffuse large B cell lymphoma patients with elevated serum lactate dehydrogenase.
The non-germinal center B cell (non-GCB) subtype of diffuse large B cell lymphoma (DLBCL) is more related to poor prognosis than the GCB subtype. To investigate the role of molecular classification according to upfront autologous hematopoietic stem cell transplantation (ASCT), we retrospectively evaluated 219 newly diagnosed high-risk DLBCL patients. Eighty-one patients were in the ASCT group, and 138 patients were in the non-ASCT group. The ASCT group yielded significantly better overall survival (OS) and progression-free survival (PFS) than the non-ASCT group (p = 0.038 and p = 0.007), and patients with the non-GCB subtype were more related to inferior PFS than those with the GCB subtype (p = 0.020). After performing age-matching by using propensity scores, upfront ASCT continued to show better OS and PFS than non-ASCT (p = 0.046 and p = 0.026). In the non-ASCT group, the non-GCB subtype showed worse OS and PFS than the GCB subtype (p = 0.039 and p = 0.007). Patients who achieved complete response showed differences in OS and PFS according to molecular subtype (p = 0.007 and p = 0.002). In the ASCT group, there were no significant differences in OS and PFS according to molecular classification (p = 0.277 and p = 0.892). In conclusion, non-GCB subtype DLBCL patients showed poor OS and PFS in the non-ASCT group while they did not show clinical significance in the ASCT group. This suggests the possibility that upfront ASCT may improve the poor prognosis of non-GCB subtype in high-risk DLBCL.


Hypereosinophilic syndrome, chronic eosinophilic leukemia, and mast cell disease.
Hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), and mast cell disease (MCD) are all considered myeloproliferative neoplasms, and diagnosis in each instance requires bone marrow examination with cytogenetic and molecular studies. HES should be distinguished from both molecularly defined and otherwise uncategorized CEL. The genes that are mutated in molecularly defined CEL include those that encode for platelet-derived growth factor receptors A and B and for fibroblast growth factor receptor 1. Diagnosis of MCD is facilitated by tryptase immunostaining and immunophenotyping to detect abnormal CD25-positive mast cells. Mutation screening for KITD816V is also advised but is not essential for the diagnosis of MCD. Asymptomatic patients with HES and no evidence of organ damage do not necessarily require immediate therapy. The same is true for patients with indolent MCD. At present, effective cytoreductive drugs for HES include corticosteroids, interferon-alpha (IFN-alpha), and hydroxyurea, imatinib for platelet-derived growth factor receptor A or B-rearranged CEL imatinib, and for MCD IFN-alpha and cladribine. In addition, a number of new drugs are currently being tested for their safety and efficacy in all 3 disorders.